Identifying AAK1 inhibitor could aid therapy discovery: Study

Scientists use protein screening to identify inhibitor for specific enzyme

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A scientist looks in a microscope in a lab alongside a rack of vials and a beaker filled with blood.

Scientists have harnessed the power of a protein-screening technology to identify a novel inhibitor of AAK1, an enzyme linked with Parkinson’s disease, a development that could speed the discovery of new therapies.

Developing inhibitors for these specific enzymes, called kinases, has proven a difficult task due to the similar structure of the more than 500 kinases in the human body.

Past studies have identified the protein kinase AAK1 as a potential therapeutic target for Parkinson’s. Kinases play a crucial role in regulating various cellular processes and can either activate or deactivate target proteins, impacting many different cellular functions. But kinases’ similar structure has been a major roadblock in the development of effective kinase inhibitors.

A team led by Hiroshi Tokumitsu, PhD, a professor at Okayama University in Japan, developed an AAK1 inhibitor called TIM-098a and confirmed its specificity using Kinobeads-based screening, a technology that works by immobilizing small kinase inhibitors on special type of beads and exposing them to numerous kinases isolated from cells. The researchers can then analyze the specificity of the inhibitor, since only the true targets of the inhibitor should remain bound to the beads after several washing steps to remove non-specific kinases.

“TIM-098a may be a promising lead compound for a more potent, selective and therapeutically useful AAK1 inhibitor,” the researchers wrote in the study, “Development of a novel AAK1 inhibitor via Kinobeads-based screening,” published in the journal Scientific Reports.

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“Through years of dedicated research into intracellular signaling mechanisms, we’ve crafted protein kinase inhibitors as potent analytical instruments for fundamental life sciences,” Tokumitsu said in a university press release.

The researchers had previously developed TIM-063, a calcium/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor. When using the Kinobeads-based screening on this inhibitor, the team found that one of TIM-063’s targets was AAK1. They conducted further analysis and discovered the active domain within AAK1 that was being recognized by TIM-063.

“Our research highlights the potential of repurposing existing kinase inhibitors as lead compounds for novel therapeutic targets,” Tokumitsu said. “[L]everaging kinase inhibitor development methods, starting with identifying enzymes that interact with existing inhibitors, promises a rapid drug discovery cycle with protein kinases as the molecular target.”

The researchers tweaked TIM-063 to develop TIM-098a, which did not inhibit CaMKK activity. They confirmed that TIM-098a inhibitory activity of AAK1 was about 35 times more potent than that of TIM-063.

While these are promising findings, the inhibitory activity of TIM-098a against AAK1 is still weaker than that of previously developed AAK1 inhibitors. “Therefore, in the future, we plan to develop an AAK1 inhibitor with more selective and potent inhibitory activity using TIM-098a as a lead compound,” the researchers wrote.

The findings open a potential new avenue of therapeutics for AAK1-dependent diseases, including Parkinson’s.

“In the era of costly and time-consuming drug discovery, our research stands to significantly contribute by facilitating the development of rapid and cost-effective enzyme inhibitors with clinical applications,” Tokumitsu said.